消癌平注射液等4种抗肿瘤中药注射剂对人肝微粒体中CYP450酶7种亚型的体外抑制作用研究

中国临床药理学与治疗学 ›› 2014, Vol. 19 ›› Issue (5): 522-527.

消癌平注射液等4种抗肿瘤中药注射剂对人肝微粒体中CYP450酶7种亚型的体外抑制作用研究

刘丽雅^1,2, 韩永龙¹, 余奇¹, 朱金辉¹, 郭澄^1,2

¹上海交通大学附属第六人民医院药剂科,上海 200233;
²上海中医药大学, 上海 201203

收稿日期:2013-09-23 修回日期:2014-05-08 出版日期:2014-05-26 发布日期:2014-06-05
通讯作者: 郭澄,男,博士,教授,主任药师,博士生导师,研究方向:中药学与临床药理学。Tel: 021-24058098 E-mail: gboss@sina.com
作者简介:刘丽雅,女,在读硕士研究生,药师,研究方向:中药学及药动学。Tel: 021-24058789 E-mail: liuliya6h@126.com
基金资助:
上海市医院协会科研基金201002029

In vitro inhibition of 4 anti-tumor traditional Chinese medicine injections on activities of 7 main cytochrome P450s in human liver microsome

LIU Li-ya^1,2, HAN Yong-long¹, YU Qi¹, ZHU Jin-hui¹, GUO Cheng^1,2

¹Department of Pharmacy,the Sixth People's Hospital Affiliated to Shanghai Jiao Tong University,Shanghai 200233,China;
²Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China

Received:2013-09-23 Revised:2014-05-08 Online:2014-05-26 Published:2014-06-05

摘要/Abstract

摘要： 目的:考察消癌平注射液等4种抗肿瘤中药注射剂对人肝微粒体CYP450酶7种亚型 CYP1A2、CYP2B6、CYP2C8、CYP2C9、CYP2C19、CYP2D6 和CYP3A4/5 的体外抑制作用。方法:消癌平注射液等4种抗肿瘤中药注射剂分别与7种CYP450酶亚型对应的混合探针药物在人肝微粒体中共同孵育,采用液相色谱-串联质谱(LC-MS/MS)法同时测定这7种探针药物的代谢产物:对乙酰氨基酚、羟基安非他酮、去甲阿莫地喹、4-羟基双氯芬酸、4-羟基美芬妥英、右啡烷和1-羟基咪达唑仑的浓度,分别代表CYP1A2、CYP2B6、CYP2C8、CYP2C9、CYP2C19、CYP2D6 和CYP3A4/5 的活性,其对CYP450酶亚型的抑制程度以IC₅₀值表示。结果:在体外人肝微粒体孵育体系中,消癌平注射液对CYP1A2、CYP2B6、CYP2C8、CYP2C9、CYP2C19和CYP3A4/5的IC₅₀值分别为 0.51%、1.34%、1.42%、0.93%、1.09%和 0.75%,艾迪注射液对CYP2C8的IC₅₀值为 0.21%;消癌平注射液对CYP2D6的IC₅₀值为 2.58%,艾迪注射液对CYP2B6、CYP2C9、CYP2C19和CYP3A4/5的IC₅₀值分别为 13.24%、16.31%、4.27%和 3.73%,华蟾素注射液对CYP1A2、CYP2B6、CYP2C8和CYP2D6的IC₅₀值分别为 3.50%、28.01%、20.32%和 32.59%,康艾注射液对CYP1A2、CYP2B6、CYP2C8、CYP2D6和CYP3A4/5的IC₅₀值分别为 2.55%、15.32%、1.44%、1.72%和 3.99%,均高于各自的日用药量浓度;在测定浓度范围内,艾迪注射液对CYP1A2和CYP2D6,华蟾素注射液对CYP2C9、CYP2C19和CYP3A4/5,康艾注射液对CYP2C9和CYP2C19的活性抑制率均小于50%。结论:在体外,正常剂量下,消癌平注射液对人CYP1A2、CYP2B6、CYP2C8、CYP2C9、CYP2C19和CYP3A4/5,艾迪注射液体对人CYP2C8均有明显抑制作用;消癌平注射液对CYP2D6,艾迪注射液对CYP2B6、CYP2C9、CYP2C19和CYP3A4/5,华蟾素注射液对CYP1A2、CYP2B6、CYP2C8和CYP2D6,康艾注射液对CYP1A2、CYP2B6、CYP2C8、CYP2D6和CYP3A4/5,均无明显抑制作用;艾迪注射液对CYP1A2和CYP2D6,华蟾素注射液对CYP2C9、CYP2C19和CYP3A4/5,康艾注射液对CYP2C9和CYP2C19,均无抑制作用。

关键词: 中药注射液, 人肝微粒体, 细胞色素P450酶, 抑制作用, 药物相互作用

Abstract: AIM: To evaluate the inhibition of 4 anti-tumor traditional Chinese medicine injections on activities of 7 main cytochrome P450s CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5 in human liver microsome in vitro.METHODS: 4 anti-tumor traditional Chinese medicine injections were incubated with human liver microsomes in the presence of seven probe substrates of CYP450 isoforms, respectively. Using LC-MS/MS method simultaneous quantification of 7 probe substrate-derived metabolites acetaminophen(CYP1A2), hydroxy-bupropin(CYP2B6), n-desethyl-amodiaquine(CYP2C8), 4'-hydroxy-diclofenac(CYP2C9), 4'-hydroxy-mephenytoin(CYP2C19), dextrorphan(CYP2D6) and 1-hydroxy-midazolam(CYP3A) to determine the activity of 7 CYP450 isoforms. The inhibitory effects were evaluated with half maximal inhibitory concentration (IC₅₀) values.RESULTS: IC₅₀ value of Xiao-Ai-Ping injection on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4/5 was 0.51%, 1.34%, 1.42%, 0.93%, 1.09%, and 0.75%, respectively. IC₅₀ value of Ai-Di injection on CYP2C8 was 0.21%. IC₅₀ value of Xiao-Ai-Ping injection on CYP2D6 was 2.58%; IC₅₀ value of Ai-Di injection on CYP2B6, CYP2C9, CYP2C19, and CYP3A4/5 was 13.24%, 16.31%, 4.27%, and 3.73%, respectively; IC₅₀ value of Hua-Chan-Su injection on CYP1A2, CYP2B6, CYP2C8, and CYP2D6 was 3.50%,28.01%, 20.32%, and 32.59%, respectively; IC₅₀ value of Kang-Ai injection on CYP1A2, CYP2B6, CYP2C8, CYP2D6, and CYP3A4/5 was 2.55%, 15.32%, 1.44%, 1.72%, and 3.99%, respctively, IC₅₀ values of them were exceeded their daily-dose concentrations, totally. The activity inhibition rates of Ai-Di injection on CYP1A2 and CYP2D6; Hua-Chan-Su injection on CYP2C9, CYP2C19 and CYP3A4/5; Kang-Ai injection on CYP2C9 and CYP2C19, were less than 50% within their concentration rangs of determinations.CONCLUSION: In vitro, Xiao-Ai-Ping injection and Ai-Di injection show significant inhibitory effect on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4/5 and CYP2C8, respectively, under normal dosage. Xiao-Ai-Ping injection, Ai-Di injection, Hua-Chan-Su injection and Kang-Ai injection show minor inhibitory effect on CYP2D6; CYP2B6, CYP2C9, CYP2C19, CYP3A4/5; CYP1A2, CYP2B6, CYP2C8, CYP2D6 and CYP1A2, CYP2B6, CYP2C8, CYP2D6, CYP3A4/5, respectively. Ai-Di injection, Hua-Chan-Su injection and Kang-Ai injection don't show inhibitory effect on CYP1A2, CYP2D6; CYP2C9, CYP2C19, CYP3A4/5 and CYP2C9, CYP2C19, respectively.

Key words: traditional Chinese medicine injection, human liver microsomes, cytochrome P450, CYP, inhibition, herb-drug interaction

中图分类号:

R965.2

刘丽雅, 韩永龙, 余奇, 朱金辉, 郭澄. 消癌平注射液等4种抗肿瘤中药注射剂对人肝微粒体中CYP450酶7种亚型的体外抑制作用研究[J]. 中国临床药理学与治疗学, 2014, 19(5): 522-527.

LIU Li-ya, HAN Yong-long, YU Qi, ZHU Jin-hui, GUO Cheng. In vitro inhibition of 4 anti-tumor traditional Chinese medicine injections on activities of 7 main cytochrome P450s in human liver microsome[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2014, 19(5): 522-527.

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